dbSNP rs10503919: NRG1:c.746-53604C>A (chr8-32542224-C-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001159999.3(NRG1):c.38-53604C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.155 in 152,104 control chromosomes in the GnomAD database, including 2,165 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.15 ( 2165 hom., cov: 33)

Consequence

NRG1
NM_001159999.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.216

Publications

3 publications found

Variant links:

Genes affected

NRG1 (HGNC:7997): (neuregulin 1) The protein encoded by this gene is a membrane glycoprotein that mediates cell-cell signaling and plays a critical role in the growth and development of multiple organ systems. An extraordinary variety of different isoforms are produced from this gene through alternative promoter usage and splicing. These isoforms are expressed in a tissue-specific manner and differ significantly in their structure, and are classified as types I, II, III, IV, V and VI. Dysregulation of this gene has been linked to diseases such as cancer, schizophrenia, and bipolar disorder (BPD). [provided by RefSeq, Apr 2016]

NRG1 Gene-Disease associations (from GenCC):

schizophrenia 6
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

NRG1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.19 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001159999.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	HGVSc	Effect	Exon Rank	Protein	UniProt
NRG1	NM_001159999.3	c.38-53604C>A	intron	N/A	NP_001153471.1	A0A494C1F5
NRG1	NM_001159995.3	c.38-53604C>A	intron	N/A	NP_001153467.1	A0A494C1F8
NRG1	NM_001160001.3	c.38-53604C>A	intron	N/A	NP_001153473.1	Q02297-11

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NRG1	ENST00000520407.5	TSL:1	c.746-53604C>A	intron	N/A	ENSP00000434640.1	Q02297-9
NRG1	ENST00000523534.5	TSL:5	c.305-53604C>A	intron	N/A	ENSP00000429067.1	H0YBA3
NRG1	ENST00000650866.1		c.38-53604C>A	intron	N/A	ENSP00000499045.1	A0A494C1F5

Frequencies

GnomAD3 genomes

AF:

0.155

AC:

23560

AN:

151986

Hom.:

2165

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0778

Gnomad AMI

AF:

0.407

Gnomad AMR

AF:

0.172

Gnomad ASJ

AF:

0.230

Gnomad EAS

AF:

0.0304

Gnomad SAS

AF:

0.108

Gnomad FIN

AF:

0.223

Gnomad MID

AF:

0.187

Gnomad NFE

AF:

0.193

Gnomad OTH

AF:

0.174

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.155

AC:

23553

AN:

152104

Hom.:

2165

Cov.:

AF XY:

0.157

AC XY:

11651

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.0776

AC:

3221

AN:

41522

American (AMR)

AF:

0.172

AC:

2629

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.230

AC:

797

AN:

3468

East Asian (EAS)

AF:

0.0301

AC:

156

AN:

5180

South Asian (SAS)

AF:

0.108

AC:

520

AN:

4816

European-Finnish (FIN)

AF:

0.223

AC:

2348

AN:

10534

Middle Eastern (MID)

AF:

0.187

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.193

AC:

13093

AN:

67984

Other (OTH)

AF:

0.172

AC:

364

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

984

1968

2951

3935

4919

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

248

496

744

992

1240

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.179

Hom.:

9845

Bravo

AF:

0.149

Asia WGS

AF:

0.0660

AC:

228

AN:

3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

3.7

(source)

DANN

Benign

0.36

PhyloP100

0.22

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over